Pain is an unpleasant sensory or emotional experience that is associated with actual or potential tissue damaging stimuli. It is always an individual and subjective sensation, which may be acute (nociceptive), elicited by noxious stimuli, or chronic pain that has outlived its usefulness to preserve tissue integrity. The perception of pain takes mainly place at cortex, and it may be suppressed in deep sedation and anesthesia by the general (global) inhibitory effects of sedative drugs and anesthetic agents. The responses to noxious stimulus may also be suppressed when the pain signal pathway is sufficiently suppressed at the subcortical level, often in the region of the brainstem and spinal cord. Both cortical and subcortical mechanisms play a role in pain management in modern surgical anesthesia or intensive care.
Analgesia refers to absence of pain or loss of sensitivity to stimulation that would normally be painful. Analgesic state is independent of the level of consciousness of the patient.
Noxious stimuli, such as pin pricks or inflammation exceeding a certain threshold stimulus level in nociceptive nerve fibers (nociceptors), cause a nociception, i.e. a neuronal signal or perception that denotes the induced pain or injury. Nociception is transmitted in the Central Nervous System (CNS) via several different ascending pathways causing responses that can be cortical pain responses or subcortical stress responses. NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) effectively relief pain at a damaged tissue site, whereas opioids selectively affect the pain pathways in the region of the spinal cord or the brainstem. Local or regional anesthetic agents, for instance those used in epidural analgesia, block both the pain and the sensory pathways in the spinal cord region.
Antinociception normally refers to the blocking or suppression of nociception in the pain pathways at the subcortical level. It may be described as subcortical analgesia, in distinction to preventing the perception of pain at the cortex, i.e. cortical analgesia.
The autonomic nervous system (ANS) is the ‘unconscious’ nervous system, which controls and regulates virtually all of our basic body functions, such as cardiac function, blood circulation and glandural secretion. The main parts of the ANS are the parasympathetical and sympathetical nervous branches. The sympathetical nervous system usually prepares us for high stress situations by speeding up the body functions. Under conditions of normal ANS regulation, the parasympathetical system restores the normal conditions in blood circulation by slowing down the heart rate. Pain, discomfort, and surgical stress may activate the sympathetical branch of the ANS and cause an increase in blood pressure, heart rate and adrenal secretions.
Neuromonitoring is a subfield of clinical patient monitoring focused on measuring various aspects of brain function and on changes therein caused by drugs commonly used to induce and maintain anesthesia in an operation room or sedation in patients under critical or intensive care.
Electroencephalography (EEG) is a well-established method for assessing brain activity by recording and analyzing the weak biopotential signals generated in the cortex of the brain with electrodes attached on the skin of the skull surface. The EEG has been in wide use for decades in basic research of the neural systems of the brain, as well as in clinical diagnosis of various neurophysiological diseases and disorders.
Electromyography (EMG) is a method for recording electrical biopotentials of muscles. In an EMG measurement, the electrodes are attached on the surface of the skin at a muscle group. An EMG signal is often recorded from the skull of the patient, whereby the recorded signal indicates both the activity of the facial muscle (fEMG) and the brain (EEG). As the frequencies of the EMG spectrum are usually high and above the frequencies of brain activity, the signal components can be separated by methods of signal processing or spectral analysis from the EEG signal.
Electrocardiography (ECG) is another well-established method for assessing cardiac function by recording and analyzing the biopotential signals generated in the heart. Electrodes are attached on the skin of the chest with more peripheral references. The ECG is commonly used for diagnosing cardiac dysfunctions, various cardiac and circulatory diseases, and arrhythmias. Heart rate (HR), often derived from the ECG waveform, is one of the most important parameters characterizing the condition of a patient.
Respiration rate is another vital sign, which is often monitored even in basic patient care. In connection with anesthesia and sedation of ventilated patients, monitoring of the respiration is often combined with monitoring of gas exchange, which includes monitoring of inhaled and exhaled oxygen, carbon dioxide and anesthetic gases. In modern gas monitors, airway pressure (AWP) and gas flows are also measured in order to improve the safety and quality of the ventilation.
Blood pressure (maintaining blood circulation) is yet another vital sign obtained from a patient. It may be monitored either non-invasively (NIBP) or invasively (InvBP) using catheters inserted in the arteries or veins. The latter techniques are continuous and they allow a detailed monitoring of the regulation of the cardiac-circulatory and pulmonary functions.
Pulse oximetry is a well-established technique for measuring oxygen saturation (SpO2) in arterial blood. SpO2 is an important parameter, nowadays often called as the fourth vital sign, which relates to the adequacy of oxygen supply to peripheral tissues and organs. Pulse oximeters also display a photoplethysmographic (PPG) pulse waveform, which can be related to tissue blood volume and blood flow, i.e. the blood circulation, at the site of the measurement, typically in finger or ear. The amplitude of a PPG waveform is a sensitive indicator of patient discomfort and pain, but it also reacts to non-noxious stimulations.
Analysis methods using the heart rate variability (HRV) are emerging techniques for diagnosing cardiac diseases, such as lack of oxygen supply to the cardiac muscle, and for characterizing the cardiac function and the condition of the patient in general. Fast changes in the heart rate are usually caused by the parasympathetical ANS control mediated in the vagal cranial nerve. Vagal control slows down the heart beat. The slow variations (<0.15 Hz) of the heart rate are mainly associated with sympathetical activity, which accelerates the heart beat. The ratio of the fast components of the HRV to the slow components of the HRV is often called the sympatho-vagal balance, which in emergency or during intense surgical stress turns to sympathetical dominance.
During the past few years, several commercial devices for measuring the level of consciousness and/or awareness in a clinical set-up during anesthesia have become available. These devices, which are based on a processed one-channel EEG signal, have been introduced by Aspect Medical (Bispectral Index), by Datex-Ohmeda (Entropy Index) and by Danmeter (an auditory evoked EEG potential monitoring device, AAI™). At present, the situation with the assessment of the cortical activity and integrity is considered satisfactory, though not resolved for all applications.
As to the central nervous system (CNS), the assessment or measurement of the suppression of the sub-cortical activity, the ANS and the integrity of subcortical evaluations is far more unsatisfactory. No commercial devices exist for this purpose. This is mainly because the sub-cortical components are not represented in any single bioelectrical or other signal, in contrast to that the EEG almost alone may represent the cortical activity. The monitoring of the adequacy of anesthesia or sedation thus—in addition to monitoring the hypnotic state of brains by EEG—call for a multi-parameter approach, which combine parameters describing the overall responsiveness of the patient to “unconscious” stimulations. This may be defined by means of the hemodynamic, motor, and endocrine stability. A promising basis for searching a multi-parameter monitoring method for sub-cortical activity can thus possibly be found from the subtle features in the common vital signs, the heart rate, the respiration rate, the blood circulation, and the blood pressure.
The sub-cortical integrity of the afferent input, ANS evaluations, and efferent autonomic output is best researched in unconscious subjects with noxious stimulations and their responses, as these are mainly processed and modulated in the brainstem and spinal levels. The responses can also be modulated (attenuated) by analgesic or antinociceptive drugs, which influence the pain pathways at the sub-cortical levels. A successful monitoring method shall thus demonstrate a clear relationship and correlation between both the effect of the analgesics on the suppression of the nociceptive responses and the intensity of the noxious stimulations on the strength or amount of the responses in the parameters.
The need for reliable monitoring of the adequacy of anesthesia is based on the quality of patient care and on economy related aspects. Balanced anesthesia reduces surgical stress and there is firm evidence that adequate analgesia decreases postoperative morbidity. Awareness during surgery with insufficient analgesia may lead to a post-traumatic stress disorder. Prolonged surgical stress sensitizes the central pain pathways, which post-operatively increases patient pain and secretion of stress hormones. Low quality pre- and intra-operative analgesia makes it difficult to select the optimal pain management strategy later on. More specifically, it may cause exposure to unwanted side effects during the recovery from the surgery. Too light an anesthesia with insufficient hypnosis causes traumatic experiences both for the patient and for the anesthesia personnel. From economical point of view, too deep an anesthesia may cause increased perioperative costs through extra use of drugs and time, and also extended time required for post-operative care. Too deep a sedation may also cause complications and prolong the usage time of expensive facilities, such as the intensive care theater.
U.S. Pat. No. 6,801,803 discloses a method and device for ascertaining the cerebral state of a patient. In this disclosure, a measure derived from EMG signal data enhances and confirms the determination of the hypnotic state made using EEG signal data. As the EMG data may be computed more frequently than the EEG data, this renders ascertaining changes in the hypnotic state of the patient more rapid. In this method, the (facial) EMG thus alone reflects the suppression of the nociceptive pathways. State entropy (SE), which is calculated in the low frequency band up to 32 Hz, is dominated by the cortical EEG activity, while response entropy (RE), which also includes the high frequencies, represents both the cortical and muscle activity. The difference RE-SE is, therefore, a measure of the (f)EMG power, which will increase at nociception and which, therefore, may be a good measure of the suppression of the pain pathways. However, the above-mentioned dependency on the medication of the patient may render the method unusable in certain situations. As the (facial) electromyography signal is affected by neuro-muscular blocking agents (NMBAs), which suppress signaling at the nerve-muscle junctions, the EMG component of the measurement may vanish and render the method unusable, if the medication of the patient includes neuro-muscular blocking agents. It shall also be emphasized that the difference RE-SE is not specific to the suppression of the pain pathways but also reflects the overall motoric activity following any arousals—that is emotional or normal sensory evoked arousals, too. For instance, when the patient is awake and not perceiving any pain or discomfort, the RE-SE difference is typically about 8-10 percent. At deep hypnosis it is obvious that only painful stimulations can cause RE to differ from SE, but it is difficult to tell at which level the transition to the only-nociception induced varying difference in the deep anesthesia takes place.
EP patent 0553162 proposes a method and apparatus for assessing the depth of anesthesia by using respiratory sinus arrhythmia (RSA) as a measure of the state of the brain. The document describes a method in which a parameter indicative of clustering of the heart beat pattern is determined from the ECG waveform relative to the beginning of each respiration cycle. This parameter is then compared with a reference value calculated using a test for randomness. The parameter is then compared with the reference value to derive a measurement of the depth of anesthesia. In particular with spontaneously breathing anesthetized patients, the clustering is proportional to the RSA, which decreases with deepening anesthesia. The heart rate changes influencing the clustering are primarily controlled by the parasympathetical branch of the ANS, and therefore, the depth of anesthesia is related to the parasympathetical activity. This, however, correlates poorly with sympathetical effects, i.e. with the pain and nociception, and therefore also poorly with the adequacy of analgesia. Furthermore, the clustering takes place differently in artificial over-pressure ventilation and in spontaneously breathing patients, as the heart rate always accelerates during the low pressure period of the respiration cycle and decelerates during the high pressure phase. The low pressure period occurs during the inspiration in case of spontaneously breathing patients and during the expiration in case of artificial ventilation. The proposed method works reasonably well for spontaneously breathing patients, who in addition have a large RSA, such as children, but often fails in connection with artificially ventilated older patients. Pain reduces RSA amplitudes, as does the deepening of anesthesia. As a result, a low value of clustering may suggest too deep an anesthesia, leading to a decrease in the level of hypnosis. This may, however, lead to a worse situation, as a result of which the patient may even wake up, especially if surgical stimulations are intense.
U.S. Pat. No. 6,120,443 also suggests a method based on a heart beat interval (ECG R-to-R peak interval, RRI) analysis to assess the depth of anesthesia. In this method, the degree of randomness of the heart beats is described by means of a fractal dimension of the series of the R-R Intervals, mathematically describing the correlation within the RRI series. High correlation is indicative of a low fractal dimension and of only very few (CNS) processes, which add irregularities in the RRI series. Low correlation and thus high randomness equals high fractal dimension, which implies that the anesthesia is light and that many processes influence the RRI series. The methods for calculating the fractal dimensions are computationally heavy. In addition, the suggested method suffers from the fact that the degree of both hypnosis and analgesia affect the fractal dimension. The orthogonality of the two measures corresponding to the cortical and subcortical activity is thus poor. Although the method was primarily suggested for measuring the hypnosis of the patient, it is probable that it will also correlate with the degree of the surgical stress, which increases hemodynamic instabilities and the fractal dimension of the RRI series. Using this method, it is thus difficult to tell, which type of a drug, an opioid or a hypnotic, is primarily needed, and whether the drug concentration should be added or reduced.
European patent application EP1273265 describes a simpler method for analyzing an RRI and a blood pressure (BP) time series. Furthermore, the method tries to make a clear distinction between the sympathetical and parasympathetical cardiovascular responses. The sympathetical responses correlating with the surgical stress increase the heart rate and blood pressure. The acceleration index of the heart rate and the index for the increase of the blood pressure are calculated using a filter, a kind of edge filter, which detects the increasing slopes in the values of RRI or BP, but neglects the decreasing values. The document suggests that these indices may be used as a measure of the adequacy of analgesia. However, the method lacks the specificity to noxious stimuli and detects also the variations caused by respiration and other increasing slopes resulting from normal sympathetical activation without noxious stimulation. For instance, when the patient is in light anesthesia, both the sympathetical and parasympathetical branch of the ANS is active and the indices show erroneously high values suggesting insufficient analgesia.
The above prior art technologies thus aim to describe the adequacy of anesthesia using a unidimensional concept for the depth of anesthesia. They do not account for separate hypnotic and analgesic components, which are orthogonal, i.e. as much independent of each other as possible, and specific to the hypnotic and analgesic medications given during anesthesia. Thus the prior art methods cannot not answer to the question, whether one should add or reduce the analgesics or hypnotics in order to restore a balanced anesthesia. All prior art technologies that are claimed to measure the adequacy of analgesia show a considerable dependence on the level of hypnosis and, consequently, at light anesthesia without any noxious stimulations show a value that is usually associated with poor analgesia. A further drawback of the prior art technologies is that the measurement values show a considerable inter-patient variability. This makes their interpretation, i.e. the interpretation of the adequacy of anesthesia, difficult.
International patent application WO 2004/034897 discloses a method and an apparatus for a plethysmographic based detection of nociception during anesthesia and sedation. In this method, predetermined pulse wave parameters are detected and compared with reference values obtained earlier by measuring the same parameters over a certain preceding time window. If a substantial change is detected in at least one pulse wave parameter, preferably in waveform amplitude, a change in another pulse wave parameter, preferably the position of the dicrotic notch, is determined. If both changes are substantial, the changes are displayed or recorded and interpreted as an indication of a nociceptive event. The method thus provides an indication of the presence of noxious stimulation. Since the method is based on detection of noxious events, i.e. short-lived changes in the signal, it cannot provide an indication of the basic level of antinociception. In other words, the relative balance between the analgesic drug effect and the level of noxious stimulation cannot be estimated or measured, which makes the method unsuitable for automatically controlling the delivery of analgesic drugs.
U.S. Patent application 2005/0010116 discloses a method and an apparatus for monitoring the condition of a patient under anesthesia or sedation In this method, a mathematical index for probability of patient comfort is calculated. The probability index is obtained as a combination of physiological parameters extracted from a plethysmographic waveform, an ECG waveform, and/or EMG power measured from patient forehead. Again, as in the above-referred WO application 2004/034897, the parameters in the probability index are referred to a certain reference value determined over a certain time window or at certain reference event. Since the index is only indicative of the probability of nociception, it cannot provide quantitative information of the level of nociception or of changes in the said level. Therefore, this algorithm is also unsuitable for automatically controlling the delivery of analgetics.
The present invention seeks to eliminate the above drawbacks by using a novel approach which enables the monitoring of the trend of the clinical state, such as the level of nociception, of a patient, and which also enables the verification of the current clinical state against a fixed scale.